Keeping the percentage of body fat above some critical minimum level is one of the most important biological aspects of our existence, says Rudolph Leibel, a professor of medicine and pediatrics and codirector of the New York Obesity Research Center and the Diabetes and Endocrinology Research Center at Columbia University. Without enough body fat, survival is impaired. So is fertility: Women need enough energy on board to feed themselves and nourish a growing fetus and then, through breast milk, a child. No wonder the body has so many mechanisms in place to protect against too much change in the downward direction. "If you perturb the system in one way, it will compensate in another," says Leibel. "It's very hard to trick Mother Nature."
Will the new drugs currently being developed for the U.S. market work any better or have fewer side effects? Two of them—Contrave, made by Orexigen Therapeutics, and Qnexa, made by Vivus—are actually combinations of existing drugs prescribed for other purposes but married with an eye to boosting effectiveness, reducing side effects, or both. Contrave, expected to be submitted for FDA consideration this year, has bupropion (the ingredient in the antidepressant Wellbutrin and the antismoking therapy Zyban) combined with naltrexone, already prescribed for drug and alcohol addiction. Bupropion seems to stimulate the brain's so-called POMC cells, with the ultimate effect of "decreasing food intake and boosting energy expenditure," says Dennis Kim, senior vice president of medical affairs at Orexigen. Naltrexone, meantime, blocks beta-endorphin, a chemical that normally ratchets down the activity of POMC. The combination leads to "longer and greater weight loss," he says.
Qnexa, which was submitted to the FDA in late December, has produced the largest weight loss in trials. It combines low doses of topiramate, an antiseizure drug, with phentermine. In higher doses, both have side effects—cognitive dulling and fatigue for topiramate and high blood pressure in phentermine—but Peter Tam, president of Vivus, says the combination of the drugs at lower doses reduces those side effects and leads to greater weight loss. (The phentermine is similar to an amphetamine, acting as a stimulant and prompting the release of a neurotransmitter that is linked to appetite suppression. The mechanism behind topiramate isn't understood.)
Lorcaserin, made by Arena Pharmaceuticals, is a new drug that stimulates the serotonin 2C receptor, found mostly in the hypothalamus. This receptor is involved in appetite and food intake. (Fenfluramine, the "bad" half of fen-phen, stimulated the closely related 2B receptor that is found in the heart, with ill effects.) "It's targeting one specific [receptor] subtype that's in a part of the brain which should only affect food intake suppression," says Dominic Behan, cofounder and chief scientific officer of Arena. The drug also seems to have few side effects. Safety will be key for the FDA, given that an obesity drug is likely to find its way into the medicine cabinets of people who may only want to lose 10 to 15 pounds; for them, the risks of carrying the extra weight aren't large, so the risks of the drug better be extremely low, says Donna Ryan, president of the Obesity Society and associate executive director for clinical research at Pennington Biomedical Research Center in Baton Rouge, La. (Her financial relationships with drug and weight-loss companies ended in 2008.)
It's important to have more options, says Michael Cowley, developer of Contrave and a professorial fellow in the department of physiology at Monash University in Australia. He and others use the analogy of the antidepressant market to describe what more drugs would likely mean: a range of different options that work well in some people and not in others—so you try something, see if it works, and move to something else if it doesn't.
Even better would be to be able to predict what will work best for a given person. "There are three reasons to eat: hunger, reward, and stress," says Robert Lustig, a pediatric endocrinologist and the director of the Weight Assessment for Teen and Child Health program at the University of California–San Francisco. And, he says, different areas of the brain are involved with each of those reasons: A region of the hypothalamus is tied to hunger, the nucleus accumbens to reward, and the amygdala to stress. An individual might have problems with one, two, or all three. "Until you determine which is the problem, you're not going to know how to target therapy appropriately," he says. Trouble is, there's no good screening tool to help doctors prescribe the correct treatment for patients.